title: Cinacalcet, a calcimimetic, prevents nonsteroidal antiinflammatory drug-induced small intestinal damage in rats.
abstract: The extracellular calcium-sensing receptor (CaSR), a G protein-coupled cell receptor cloned from bovine parathyroid, has been demonstrated to play a regulatory role in various functions of the gastrointestinal tract. In the present study, we examined the effect of cinacalcet, a drug that acts as a calcimimetic through the allosteric activation of CaSR, on the loxoprofen-induced small intestinal lesions and investigated the mechanisms involved in the protective action. Male Sprague-Dawley rats were used without fasting. The animals were administered loxoprofen p.o. and euthanized 24 hours later and the intestinal mucosa was examined for lesions. Cinacalcet was given p.o. twice, 30 min before and 6 h after loxoprofen. Loxoprofen caused hemorrhagic lesions in the small intestine, accompanied by the upregulation of enterobacterial invasion, myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS)/tumor necrosis factor α (TNF-α) expression as well as the downregulation of Muc2 expression. Prior administration of cinacalcet dose-dependently and significantly reduced the severity of these lesions in response to loxoprofen, with concomitant suppression of the changes in bacterial invasion, iNOS/TNF-α as well as Muc2 expression, and myeloperoxidase activity. Cinacalcet also significantly reversed a decrease in mucus secretion and fluid secretion in the small intestine caused by loxoprofen, but had no effect on the intestinal hypermotility or prostaglandin E₂ deficiency caused by loxoprofen. These results suggest that cinacalcet protects the small intestine against loxoprofen-induced damage, and this effect may be functionally associated with an increase in fluid secretion and a reversal of downregulation of Muc2 expression caused by loxoprofen, resulting in suppression of bacterial invasion and iNOS/TNF-α expression, the major pathogenic events in nonsteroidal antiinflammatory drugs-induced small intestinal ulceration.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan. takeuchi@mb.kyoto-phu.ac.jp.
authors.forename: S
authors.initials: S
authors.lastname: Hayashi
authors.forename: N
authors.initials: N
authors.lastname: Kurata
authors.forename: E
authors.initials: E
authors.lastname: Kitahirachi
authors.forename: Y
authors.initials: Y
authors.lastname: Nishimura
authors.forename: K
authors.initials: K
authors.lastname: Amagase
authors.forename: T
authors.initials: T
authors.lastname: Yano
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D058491:Bacterial Load; D000069449:Cinacalcet; D015232:Dinoprostone / Q000378:metabolism; D004755:Enterobacteriaceae / Q000302:isolation & purification; D007410:Intestinal Diseases / Q000139:chemically induced / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008297:Male; D055262:Mucin-2 / Q000235:genetics; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D010666:Phenylpropionates / Q000009:adverse effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000819:agonists* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C524628:Muc2 protein, rat; D055262:Mucin-2; D009281:Naphthalenes; D009842:Oligopeptides; D010666:Phenylpropionates; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D014409:Tumor Necrosis Factor-alpha; C576321:glutamyl-valyl-glycine; C040656:loxoprofen; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015232:Dinoprostone; D000069449:Cinacalcet